Many deadly microbes have learned that the key to launching an infection is not to kill your host - at least not too quickly. Now, scientists at the University of California, Berkeley, have discovered how one microbe, Listeria monocytogenes, is able to manage this.

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Now, scientists at the University of California, Berkeley, have discovered how one microbe, Listeria monocytogenes, is able to manage this.

In a paper in this week's issue of Science, Daniel A. Portnoy, professor of molecular and cell biology in the campus's College of Letters & Science and professor of infectious diseases in the School of Public Health, along with post-doctoral fellow Amy L. Decatur, describe the trick these bacteria use to live comfortably inside a cell until they're ready to break out and spread the infection to other cells.

The finding could have implications beyond this one bacteria, which causes a deadly disease called listeriosis. The world's top three infectious killers - AIDS, tuberculosis and malaria - all are caused by pathogens that ensconce themselves snugly inside cells and live to wreak havoc. Yet, these intracellular pathogens have been hard to study, Portnoy said.

"There are no effective vaccines for any of these diseases, in part because it is difficult to study intracellular pathogens," he said. "Listeria is a great model system for studying the host-pathogen interaction of these intracellular bugs."

Listeria is a common but deadly bacterium that in recent years has made headlines as a contaminant of hot dogs, cheese, cole slaw and other food stuffs, causing more than two thousand infections every year and 500 deaths. Though it hits immune-compromised people the hardest, its overall fatality rate is about 20 percent.

Listeria bacteria establish an infection by inducing immune system cells, mostly scavenger cells called phagocytes, to corral and swallow them, so that they end up encased in a bubble within the body of the cell. The bacteria would be benign if they remained isolated in the vacuole, because the cell can kill them there. But they eventually break out and take over the host cell's machinery to spread the infection. What makes Listeria virulent is a pore-forming toxin that allows the bacteria to break through the wall of the vacuole and enter the cell's innards, Portnoy said.

A big question has always been why the toxin, listeriolysin O, doesn't also rupture and kill the cell, exposing the bacteria to the immune system.

Several years ago, a post-doctoral fellow in Portnoy's lab compared listeriolysin O to a similar pore-forming toxin called perfringolysin O, from the extracellular bacteria Clostridium perfringens, which cause gangrene. Sian Jones and Portnoy found that if they substituted perfringolysin O for Listeria's normal toxin, the altered bacteria were able to punch their way out of a vacuole, but then they killed the host cell. This made Listeria totally avirulent, Portnoy said, because the immune system efficiently mopped up the exposed bacteria.

Portnoy and Decatur compared the genetic sequences of the two toxins and found that listeriolysin O contains an extra bit of protein that looks just like a tag found in a range of organisms from yeast to humans, and which often tells the cell a protein is trash and should be chopped up and recycled. The tag is referred to as a PEST sequence, signifying the four amino acids characteristic of the tags.

Listeria bacteria apparently stole the tag and placed it on the toxin so that the host cell's clean-up crew recognizes it and targets it for destruction before it has a chance to make pinholes in the cell membrane.

"It's a great example of how bacteria have taken advantage of the host's biology to enhance their pathogenicity," Portnoy said.

The two scientists elegantly demonstrated how critical this PEST sequence is to the virulence of Listeria. When they mutated the PEST tag so the cell no longer recognized it, the mutant bacteria quickly killed off the host cells. The mutant Listeria proved 10,000 times less virulent in mice than the wild Listeria bacteria. Apparently, immune system cells eliminated the mutant bacteria once they killed off their host cell.

"In order to survive, the pathogen must maintain a protected niche within the host cell," Decatur said. "To achieve this, the toxin has co-opted the cell's own machinery, sprouting a tag that says, 'Please get rid of me.'"

Portnoy and his colleagues have discovered the role played by another important protein in the Listeria lifecycle. Once the bacteria break free of their protective vacuoles, they take over the cell machinery and do something amazing. They generate comet-like tails that push them around the cell like a speedboat. Eventually, they slam into the cell membrane and pop from one cell into the next, spreading the infection.

While the comet tails have been observed and photographed for more than a decade (see http://cmgm.stanford.edu/theriot/movies.htm for movies), two years ago Matthew D. Welch, an assistant professor of molecular and cell biology at UC Berkeley, and his colleagues reported details of how the tail is made.

They found that the tail is produced when a protein on the surface of the bacteria, ActA, interacts with a complex of host cell proteins called the Arp2/3 complex. The result is rapid polymerization of a skeletal protein called actin that piles up and physically propels the newly formed bacteria around the cell.

Welch, Portnoy and graduate student Justin Skoble dissected ActA even further, and in the August 7 issue of The Journal of Cell Biology reported details of how different parts of the protein carry out different functions, all of which are critical to the pathogen's virulence.

"What's elegant about this is that over millions of years, the bacteria have evolved individual proteins capable of exploiting complex processes that control host cell biology," Portnoy said.

###

The research was funded by the National Institutes of Health. Portnoy is one of several hundred UC Berkeley researchers involved with the campus's Health Sciences Initiative, which draws scientists from a broad range of fields to tackle today's health problems.

NOTE: For further information, see Portnoy's Web site at http://mcb.berkeley.edu/labs/portnoy/index.html.

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